Concentraciones de oxígeno intermitentes tienen impacto en el desarrollo postnatal temprano de ratas Sprague-Dawley: efectos en CA1 del hipocampo / Intermittent oxygen concentrations have an impact on the early postnatal development of Sprague-Dawley rats: effects on hippocampal CA1

El periodo postnatal temprano se caracteriza por rápido crecimiento cerebral, posiblemente relacionado con variaciones del oxígeno tisular. Esto ha motivado el estudio de protocolos que suministran diferentes concentraciones de oxígeno intermitentes, para observar sus efectos morfológicos y cerebrales. Se utilizaron 52 crías de ratas Sprague Dawley, distribuidas en igual número a cuatro grupos experimentales, Control (C, 21 %O2), Hipoxia Intermitente (HI, 11 %O2), Hiperoxia Intermitente (HOI, 30 %O2) e Hipoxia Hiperoxia Intermitente (HHI, 11 % -30 %O2). Los protocolos consideraron 5 ciclos de 5 minutos de dosificación, durante 50 minutos diarios. Se realizó en una cámara semihermética entre los días 5 al 11 postnatales. Las evaluaciones de crecimiento corporal y cuantificación neuronal, se realizaron en las crías macho, en el día 28 postnatal. El peso corporal en el grupo hipoxia intermitente mostró diferencias significativas respecto al grupo hiperoxia intermitente (HI vs HOI, p<0,01) y al grupo hipoxia-hiperoxia Intermitente (HI vs HHI, p< 0,001). La talla corporal disminuyó en el grupo hipoxia-hiperoxia intermitente con diferencias significativas respecto del grupo control (C vs HHI, p<0,05) y respecto del grupo hipoxia intermitente (HHI vs HI, p< 0,01). El conteo neuronal en el área CA1 del hipocampo aumentó en el grupo hipoxia intermitente con diferencias significativas respecto a los grupos control (C vs HI; p<0,05), al grupo hiperoxia intermitente (HI vs HOI; p<0,001) y al grupo hipoxia-hiperoxia intermitente (HI vs HHI; p<0,001). Finalmente, el grupo hipoxia- hiperoxia Intermitente disminuyó significativamente en la cantidad de neuronas en comparación al grupo hiperoxia intermitente (HHI vs HOI; p<0,001). La hipoxia intermitente mostró resultados beneficiosos en el crecimiento corporal y cantidad de neuronas en el área CA1 del hipocampo, en contraste, la hipoxia hiperoxia intermitente experimentó resultados adversos con disminución de estas variables, en el periodo postnatal temprano de la rata.

SUMMARY: The early postnatal period is characterized by rapid brain growth, possibly related to variations in tissue oxygen. This has motivated the study of protocols that supply different intermittent oxygen concentrations, to observe their morphological and cerebral effects. Fifty-two pups Sprague-Dawley rats were distributed in equal numbers into four experimental groups, Control (C, 21 %O), Intermittent Hypoxia (HI, 11 %O), Intermittent Hyperoxia (HOI, 30 %O2) and Intermittent Hypoxia Hyperoxia (HHI, 11 % - 30 %O2). The protocols considered 5 cycles of 5 min of dosing, for 50 min diary. It was performed in a semi- hermetic chamber between 5 to 11postnatal days. The evaluations of body growth and neuronal quantification were analyzed in male pups, on postnatal day 28. Body weight in the intermittent hypoxia group showed significant differences compared to the intermittent hyperoxia group (HI vs HOI, p<0.01) and the intermittent hypoxia- hyperoxia group (HI vs HHI, p<0.001). Body size decreased in the Intermittent hypoxia-hyperoxia group with significant differences compared to the control group (C vs HHI, p<0.05) and with respect to the intermittent hypoxia group (HHI vs HI, p<0.01). The neuronal count in the area CA1 of the hippocampus increased in the intermittent hypoxia group with significant differences compared to the control groups (C vs HI; p<0.05), to the intermittent hyperoxia group (HI vs HOI; p< 0.001) and the intermittent hypoxia-hyperoxia group (HI vs HHI; p<0.001). Finally, the intermittent hypoxia- hyperoxia group decreased significantly in the number of neurons compared with the intermittent hyperoxia group (HHI vs HOI; p<0.001). Intermittent hypoxia showed beneficial results in body growth and the number of neurons in the CA1 area of the hippocampus, in contrast, intermittent hypoxia-hyperoxia experienced adverse results with a decrease in these variables, in the early postnatal period of the rat.

Relationship between Anti-SARS-CoV-2 S Abs and IFN-λ3 Levels in the Administration of Oxygen following COVID-19 Vaccination.

Although the effectiveness of vaccination at preventing hospitalization and severe coronavirus disease (COVID-19) has been reported in numerous studies, the detailed mechanism of innate immunity occurring in host cells by breakthrough infection is unclear. One hundred forty-six patients were included in this study. To determine the effects of vaccination and past infection on innate immunity following SARS-CoV-2 infection, we analyzed the relationship between anti-SARS-CoV-2 S Abs and biomarkers associated with the deterioration of COVID-19 (IFN-λ3, C-reactive protein, lactate dehydrogenase, ferritin, procalcitonin, and D-dimer). Anti-S Abs were classified into two groups according to titer: high titer (≥250 U/ml) and low titer (<250 U/ml). A negative correlation was observed between anti-SARS-CoV-2 S Abs and IFN-λ3 levels (r = -0.437, p < 0.001). A low titer of anti-SARS-CoV-2 S Abs showed a significant association with oxygen demand in patients, excluding aspiration pneumonia. Finally, in a multivariate analysis, a low titer of anti-SARS-CoV-2 S Abs was an independent risk factor for oxygen demand, even after adjusting for age, sex, body mass index, aspiration pneumonia, and IFN-λ3 levels. In summary, measuring anti-SARS-CoV-2 S Abs and IFN-λ3 may have clinical significance for patients with COVID-19. To predict the oxygen demand of patients with COVID-19 after hospitalization, it is important to evaluate the computed tomography findings to determine whether the pneumonia is the result of COVID-19 or aspiration pneumonia.

An Analysis of the Effect of Noninvasive Positive Pressure Ventilation on Patients with Respiratory Failure Complicated by Diabetes Mellitus.

Objective: To observe the clinical effectiveness of noninvasive positive pressure ventilation in patients with respiratory failure complicated by diabetes. Methods: From May 2021 to May 2022, 90 patients with respiratory failure complicated by diabetes treated in our hospital were recruited and randomly assigned to receive either medication (control group) or noninvasive positive pressure ventilation (study group), with 45 patients in each group. The clinical endpoint was therapeutic outcomes. Results: Noninvasive positive pressure ventilation resulted in significantly lower Self-Rating Anxiety Scale (SAS) and Self-Rating Depression Scale (SDS) scores versus medications (P < 0.05). Patients with noninvasive positive pressure ventilation showed better pulmonary function indices versus those with medications (P > 0.05). There was no significant difference in arterial oxygen (PaO2), carbon dioxide partial pressure (PaCO2), and arterial oxygen pressure/inspired fraction of O2 (PaO2/FiO2) between the two groups prior to the intervention (P > 0.05). However, patients in the study group had significantly elevated PaO2 and PaO2/FiO2 and lower PaCO2 levels than those in the control group (P < 0.05). Following the intervention, noninvasive positive pressure ventilation resulted in significantly lower inflammatory factor levels versus medications (P > 0.05). After the intervention, markedly better glucose control was observed in the study group versus the control group (P < 0.05). The incidence of complications in the control group was 2.38%, which was significantly lower than that of the control group (16.67) (P < 0.05). Conclusion: Noninvasive positive pressure ventilation effectively suppresses the inflammatory response, improves the blood gas analysis index, and eliminates the negative emotions of patients, thereby maintaining hemodynamic stability and improving clinical efficacy with a better safety profile. Further studies are recommended prior to clinical promotion.

Oxygen-Saturation Targets for Critically Ill Adults Receiving Mechanical Ventilation.

BACKGROUND: Invasive mechanical ventilation in critically ill adults involves adjusting the fraction of inspired oxygen to maintain arterial oxygen saturation. The oxygen-saturation target that will optimize clinical outcomes in this patient population remains unknown. METHODS: In a pragmatic, cluster-randomized, cluster-crossover trial conducted in the emergency department and medical intensive care unit at an academic center, we assigned adults who were receiving mechanical ventilation to a lower target for oxygen saturation as measured by pulse oximetry (Spo2) (90%; goal range, 88 to 92%), an intermediate target (94%; goal range, 92 to 96%), or a higher target (98%; goal range, 96 to 100%). The primary outcome was the number of days alive and free of mechanical ventilation (ventilator-free days) through day 28. The secondary outcome was death by day 28, with data censored at hospital discharge. RESULTS: A total of 2541 patients were included in the primary analysis. The median number of ventilator-free days was 20 (interquartile range, 0 to 25) in the lower-target group, 21 (interquartile range, 0 to 25) in the intermediate-target group, and 21 (interquartile range, 0 to 26) in the higher-target group (P = 0.81). In-hospital death by day 28 occurred in 281 of the 808 patients (34.8%) in the lower-target group, 292 of the 859 patients (34.0%) in the intermediate-target group, and 290 of the 874 patients (33.2%) in the higher-target group. The incidences of cardiac arrest, arrhythmia, myocardial infarction, stroke, and pneumothorax were similar in the three groups. CONCLUSIONS: Among critically ill adults receiving invasive mechanical ventilation, the number of ventilator-free days did not differ among groups in which a lower, intermediate, or higher Spo2 target was used. (Supported by the National Heart, Lung, and Blood Institute and others; PILOT ClinicalTrials.gov number, NCT03537937.).

Effect of Helmet Noninvasive Ventilation vs Usual Respiratory Support on Mortality Among Patients With Acute Hypoxemic Respiratory Failure Due to COVID-19: The HELMET-COVID Randomized Clinical Trial.

Importance: Helmet noninvasive ventilation has been used in patients with COVID-19 with the premise that helmet interface is more effective than mask interface in delivering prolonged treatments with high positive airway pressure, but data about its effectiveness are limited. Objective: To evaluate whether helmet noninvasive ventilation compared with usual respiratory support reduces mortality in patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. Design, Setting, and Participants: This was a multicenter, pragmatic, randomized clinical trial that was conducted in 8 sites in Saudi Arabia and Kuwait between February 8, 2021, and November 16, 2021. Adult patients with acute hypoxemic respiratory failure (n = 320) due to suspected or confirmed COVID-19 were included. The final follow-up date for the primary outcome was December 14, 2021. Interventions: Patients were randomized to receive helmet noninvasive ventilation (n = 159) or usual respiratory support (n = 161), which included mask noninvasive ventilation, high-flow nasal oxygen, and standard oxygen. Main Outcomes and Measures: The primary outcome was 28-day all-cause mortality. There were 12 prespecified secondary outcomes, including endotracheal intubation, barotrauma, skin pressure injury, and serious adverse events. Results: Among 322 patients who were randomized, 320 were included in the primary analysis, all of whom completed the trial. Median age was 58 years, and 187 were men (58.4%). Within 28 days, 43 of 159 patients (27.0%) died in the helmet noninvasive ventilation group compared with 42 of 161 (26.1%) in the usual respiratory support group (risk difference, 1.0% [95% CI, -8.7% to 10.6%]; relative risk, 1.04 [95% CI, 0.72-1.49]; P = .85). Within 28 days, 75 of 159 patients (47.2%) required endotracheal intubation in the helmet noninvasive ventilation group compared with 81 of 161 (50.3%) in the usual respiratory support group (risk difference, -3.1% [95% CI, -14.1% to 7.8%]; relative risk, 0.94 [95% CI, 0.75-1.17]). There were no significant differences between the 2 groups in any of the prespecified secondary end points. Barotrauma occurred in 30 of 159 patients (18.9%) in the helmet noninvasive ventilation group and 25 of 161 (15.5%) in the usual respiratory support group. Skin pressure injury occurred in 5 of 159 patients (3.1%) in the helmet noninvasive ventilation group and 10 of 161 (6.2%) in the usual respiratory support group. There were 2 serious adverse events in the helmet noninvasive ventilation group and 1 in the usual respiratory support group. Conclusions and Relevance: Results of this study suggest that helmet noninvasive ventilation did not significantly reduce 28-day mortality compared with usual respiratory support among patients with acute hypoxemic respiratory failure due to COVID-19 pneumonia. However, interpretation of the findings is limited by imprecision in the effect estimate, which does not exclude potentially clinically important benefit or harm. Trial Registration: ClinicalTrials.gov Identifier: NCT04477668.

Effect of High-Flow Nasal Cannula Oxygen vs Standard Oxygen Therapy on Mortality in Patients With Respiratory Failure Due to COVID-19: The SOHO-COVID Randomized Clinical Trial.

Importance: The benefit of high-flow nasal cannula oxygen (high-flow oxygen) in terms of intubation and mortality in patients with respiratory failure due to COVID-19 is controversial. Objective: To determine whether the use of high-flow oxygen, compared with standard oxygen, could reduce the rate of mortality at day 28 in patients with respiratory failure due to COVID-19 admitted in intensive care units (ICUs). Design, Setting, and Participants: The SOHO-COVID randomized clinical trial was conducted in 34 ICUs in France and included 711 patients with respiratory failure due to COVID-19 and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen equal to or below 200 mm Hg. It was an ancillary trial of the ongoing original SOHO randomized clinical trial, which was designed to include patients with acute hypoxemic respiratory failure from all causes. Patients were enrolled from January to December 2021; final follow-up occurred on March 5, 2022. Interventions: Patients were randomly assigned to receive high-flow oxygen (n = 357) or standard oxygen delivered through a nonrebreathing mask initially set at a 10-L/min minimum (n = 354). Main Outcomes and Measures: The primary outcome was mortality at day 28. There were 13 secondary outcomes, including the proportion of patients requiring intubation, number of ventilator-free days at day 28, mortality at day 90, mortality and length of stay in the ICU, and adverse events. Results: Among the 782 randomized patients, 711 patients with respiratory failure due to COVID-19 were included in the analysis (mean [SD] age, 61 [12] years; 214 women [30%]). The mortality rate at day 28 was 10% (36/357) with high-flow oxygen and 11% (40/354) with standard oxygen (absolute difference, -1.2% [95% CI, -5.8% to 3.4%]; P = .60). Of 13 prespecified secondary outcomes, 12 showed no significant difference including in length of stay and mortality in the ICU and in mortality up until day 90. The intubation rate was significantly lower with high-flow oxygen than with standard oxygen (45% [160/357] vs 53% [186/354]; absolute difference, -7.7% [95% CI, -14.9% to -0.4%]; P = .04). The number of ventilator-free days at day 28 was not significantly different between groups (median, 28 [IQR, 11-28] vs 23 [IQR, 10-28] days; absolute difference, 0.5 days [95% CI, -7.7 to 9.1]; P = .07). The most common adverse events were ventilator-associated pneumonia, occurring in 58% (93/160) in the high-flow oxygen group and 53% (99/186) in the standard oxygen group. Conclusions and Relevance: Among patients with respiratory failure due to COVID-19, high-flow nasal cannula oxygen, compared with standard oxygen therapy, did not significantly reduce 28-day mortality. Trial Registration: ClinicalTrials.gov Identifier: NCT04468126.

[Xenon post-conditioning protects against spinal cord ischemia-reperfusion injury in rats by downregulating mTOR pathway and inhibiting endoplasmic reticulum stress-induced neuronal apoptosis].

OBJECTIVE: The purpose of this study was to determine whether xenon post-conditioning affects mTOR signaling as well as endoplasmic reticulum stress (ERS)-apoptosis pathway in rats with spinal cord ischemia/reperfusion injury. METHODS: Fifty male rats were randomized equally into sham-operated group (Sham group), I/R model group (I/R group), I/R model+ xenon post-conditioning group (Xe group), I/R model+rapamycin (a mTOR signaling pathway inhibitor) treatment group (I/R+ Rapa group), and I/R model + xenon post- conditioning with rapamycin treatment group (Xe + Rapa group).. In the latter 4 groups, SCIRI was induced by clamping the abdominal aorta for 85 min followed by reperfusion for 4 h. Rapamycin (or vehicle) was administered by daily intraperitoneal injection (4 mg/kg) for 3 days before SCIRI, and xenon post-conditioning by inhalation of 1∶1 mixture of xenon and oxygen for 1 h at 1 h after initiation of reperfusion; the rats without xenon post-conditioning were given inhalation of nitrogen and oxygen (1∶ 1). After the reperfusion, motor function and histopathologic changes in the rats were examined. Western blotting and real-time PCR were used to detect the protein and mRNA expressions of GRP78, ATF6, IRE1α, PERK, mTOR, p-mTOR, Bax, Bcl-2 and caspase-3 in the spinal cord. RESULTS: The rats showed significantly lowered hind limb motor function following SCIRI (P < 0.01) with a decreased count of normal neurons, increased mRNA and protein expressions of GRP78, ATF6, IRE1α, PERK, and caspase-3, and elevated p-mTOR/mTOR ratio and Bax/Bcl-2 ratio (P < 0.01). Xenon post-conditioning significantly decreased the mRNA and protein levels of GRP78, ATF6, IRE1α, PERK and caspase-3 (P < 0.05 or 0.01) and reduced p-mTOR/mTOR and Bax/Bcl-2 ratios (P < 0.01) in rats with SCIRI; the mRNA contents and protein levels of GRP78 and ATF6 were significantly decreased in I/R+Rapa group (P < 0.01). Compared with those in Xe group, the rats in I/R+Rapa group and Xe+Rapa had significantly lowered BBB and Tarlov scores of the hind legs (P < 0.01), and caspase-3 protein level and Bax/Bcl-2 ratio were significantly lowered in Xe+Rapa group (P < 0.05 or 0.01). CONCLUSION: By inhibiting ERS and neuronal apoptosis, xenon post- conditioning may have protective effects against SCIRI in rats. The mTOR signaling pathway is partially involved in this process.

Cost-effectiveness and sustainability of improved hospital oxygen systems in Nigeria.

INTRODUCTION: Improving hospital oxygen systems can improve quality of care and reduce mortality for children, but we lack data on cost-effectiveness or sustainability. This study evaluated medium-term sustainability and cost-effectiveness of the Nigeria Oxygen Implementation programme. METHODS: Prospective follow-up of a stepped-wedge trial involving 12 secondary-level hospitals. Cross-sectional facility assessment, clinical audit (January-March 2021), summary admission data (January 2018-December 2020), programme cost data. INTERVENTION: pulse oximetry introduction followed by solar-powered oxygen system installation with clinical and technical training and support. PRIMARY OUTCOMES: (i) proportion of children screened with pulse oximetry; (ii) proportion of hypoxaemic (SpO2 <90%) children who received oxygen. Comparison across three time periods: preintervention (2014-2015), intervention (2016-2017) and follow-up (2018-2020) using mixed-effects logistic regression. Calculated cost-effectiveness of the intervention on child pneumonia mortality using programme costs, recorded deaths and estimated counterfactual deaths using effectiveness estimates from our effectiveness study. Reported cost-effectiveness over the original 2-year intervention period (2016-2017) and extrapolated over 5 years (2016-2020). RESULTS: Pulse oximetry coverage for neonates and children remained high during follow-up (83% and 81%) compared with full oxygen system period (94% and 92%) and preintervention (3.9% and 2.9%). Oxygen coverage for hypoxaemic neonates/children was similarly high (94%/88%) compared with full oxygen system period (90%/82%). Functional oxygen sources were present in 11/12 (92%) paediatric areas and all (8/8) neonatal areas; three-quarters (15/20) of wards had a functional oximeter. Of 32 concentrators deployed, 23/32 (72%) passed technical testing and usage was high (median 10 797 hours). Estimated 5-year cost-effectiveness US$86 per patient treated, $2694-4382 per life saved and $82-125 per disability-adjusted life year-averted. We identified practical issues for hospitals and Ministries of Health wishing to adapt and scale up pulse oximetry and oxygen. CONCLUSION: Hospital-level improvements to oxygen and pulse oximetry systems in Nigerian hospitals have been sustained over the medium-term and are a highly cost-effective child pneumonia intervention.

Oxygen Targets in Comatose Survivors of Cardiac Arrest.

BACKGROUND: The appropriate oxygenation target for mechanical ventilation in comatose survivors of out-of-hospital cardiac arrest is unknown. METHODS: In this randomized trial with a 2-by-2 factorial design, we randomly assigned comatose adults with out-of-hospital cardiac arrest in a 1:1 ratio to either a restrictive oxygen target of a partial pressure of arterial oxygen (Pao2) of 9 to 10 kPa (68 to 75 mm Hg) or a liberal oxygen target of a Pao2 of 13 to 14 kPa (98 to 105 mm Hg); patients were also assigned to one of two blood-pressure targets (reported separately). The primary outcome was a composite of death from any cause or hospital discharge with severe disability or coma (Cerebral Performance Category [CPC] of 3 or 4; categories range from 1 to 5, with higher values indicating more severe disability), whichever occurred first within 90 days after randomization. Secondary outcomes were neuron-specific enolase levels at 48 hours, death from any cause, the score on the Montreal Cognitive Assessment (ranging from 0 to 30, with higher scores indicating better cognitive ability), the score on the modified Rankin scale (ranging from 0 to 6, with higher scores indicating greater disability), and the CPC at 90 days. RESULTS: A total of 789 patients underwent randomization. A primary-outcome event occurred in 126 of 394 patients (32.0%) in the restrictive-target group and in 134 of 395 patients (33.9%) in the liberal-target group (hazard ratio, 0.95; 95% confidence interval, 0.75 to 1.21; P = 0.69). At 90 days, death had occurred in 113 patients (28.7%) in the restrictive-target group and in 123 (31.1%) in the liberal-target group. On the CPC, the median category was 1 in the two groups; on the modified Rankin scale, the median score was 2 in the restrictive-target group and 1 in the liberal-target group; and on the Montreal Cognitive Assessment, the median score was 27 in the two groups. At 48 hours, the median neuron-specific enolase level was 17 µg per liter in the restrictive-target group and 18 µg per liter in the liberal-target group. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Targeting of a restrictive or liberal oxygenation strategy in comatose patients after resuscitation for cardiac arrest resulted in a similar incidence of death or severe disability or coma. (Funded by the Novo Nordisk Foundation; BOX ClinicalTrials.gov number, NCT03141099.).

Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses.

BACKGROUND: The Solidarity trial among COVID-19 inpatients has previously reported interim mortality analyses for four repurposed antiviral drugs. Lopinavir, hydroxychloroquine, and interferon (IFN)-ß1a were discontinued for futility but randomisation to remdesivir continued. Here, we report the final results of Solidarity and meta-analyses of mortality in all relevant trials to date. METHODS: Solidarity enrolled consenting adults (aged ≥18 years) recently hospitalised with, in the view of their doctor, definite COVID-19 and no contraindication to any of the study drugs, regardless of any other patient characteristics. Participants were randomly allocated, in equal proportions between the locally available options, to receive whichever of the four study drugs (lopinavir, hydroxychloroquine, IFN-ß1a, or remdesivir) were locally available at that time or no study drug (controls). All patients also received the local standard of care. No placebos were given. The protocol-specified primary endpoint was in-hospital mortality, subdivided by disease severity. Secondary endpoints were progression to ventilation if not already ventilated, and time-to-discharge from hospital. Final log-rank and Kaplan-Meier analyses are presented for remdesivir, and are appended for all four study drugs. Meta-analyses give weighted averages of the mortality findings in this and all other randomised trials of these drugs among hospital inpatients. Solidarity is registered with ISRCTN, ISRCTN83971151, and ClinicalTrials.gov, NCT04315948. FINDINGS: Between March 22, 2020, and Jan 29, 2021, 14 304 potentially eligible patients were recruited from 454 hospitals in 35 countries in all six WHO regions. After the exclusion of 83 (0·6%) patients with a refuted COVID-19 diagnosis or encrypted consent not entered into the database, Solidarity enrolled 14 221 patients, including 8275 randomly allocated (1:1) either to remdesivir (ten daily infusions, unless discharged earlier) or to its control (allocated no study drug although remdesivir was locally available). Compliance was high in both groups. Overall, 602 (14·5%) of 4146 patients assigned to remdesivir died versus 643 (15·6%) of 4129 assigned to control (mortality rate ratio [RR] 0·91 [95% CI 0·82-1·02], p=0·12). Of those already ventilated, 151 (42·1%) of 359 assigned to remdesivir died versus 134 (38·6%) of 347 assigned to control (RR 1·13 [0·89-1·42], p=0·32). Of those not ventilated but on oxygen, 14·6% assigned to remdesivir died versus 16·3% assigned to control (RR 0·87 [0·76-0·99], p=0·03). Of 1730 not on oxygen initially, 2·9% assigned to remdesivir died versus 3·8% assigned to control (RR 0·76 [0·46-1·28], p=0·30). Combining all those not ventilated initially, 11·9% assigned to remdesivir died versus 13·5% assigned to control (RR 0·86 [0·76-0·98], p=0·02) and 14·1% versus 15·7% progressed to ventilation (RR 0·88 [0·77-1·00], p=0·04). The non-prespecified composite outcome of death or progression to ventilation occurred in 19·6% assigned to remdesivir versus 22·5% assigned to control (RR 0·84 [0·75-0·93], p=0·001). Allocation to daily remdesivir infusions (vs open-label control) delayed discharge by about 1 day during the 10-day treatment period. A meta-analysis of mortality in all randomised trials of remdesivir versus no remdesivir yielded similar findings. INTERPRETATION: Remdesivir has no significant effect on patients with COVID-19 who are already being ventilated. Among other hospitalised patients, it has a small effect against death or progression to ventilation (or both). FUNDING: WHO.

Supplemental oxygen administration during mechanical ventilation reduces diaphragm blood flow and oxygen delivery.

During mechanical ventilation (MV), supplemental oxygen (O2) is commonly administered to critically ill patients to combat hypoxemia. Previous studies demonstrate that hyperoxia exacerbates MV-induced diaphragm oxidative stress and contractile dysfunction. Whereas normoxic MV (i.e., 21% O2) diminishes diaphragm perfusion and O2 delivery in the quiescent diaphragm, the effect of MV with 100% O2 is unknown. We tested the hypothesis that MV supplemented with hyperoxic gas (100% O2) would increase diaphragm vascular resistance and reduce diaphragmatic blood flow and O2 delivery to a greater extent than MV alone. Female Sprague-Dawley rats (4-6 mo) were randomly divided into two groups: 1) MV + 100% O2 followed by MV + 21% O2 (n = 9) or 2) MV + 21% O2 followed by MV + 100% O2 (n = 10). Diaphragmatic blood flow (mL/min/100 g) and vascular resistance were determined, via fluorescent microspheres, during spontaneous breathing (SB), MV + 100% O2, and MV + 21% O2. Compared with SB, total diaphragm vascular resistance was increased, and blood flow was decreased with both MV + 100% O2 and MV + 21% O2 (all P < 0.05). Medial costal diaphragmatic blood flow was lower with MV + 100% O2 (26 ± 6 mL/min/100 g) versus MV + 21% O2 (51 ± 15 mL/min/100 g; P < 0.05). Second, the addition of 100% O2 during normoxic MV exacerbated the MV-induced reductions in medial costal diaphragm perfusion (23 ± 7 vs. 51 ± 15 mL/min/100 g; P < 0.05) and O2 delivery (3.4 ± 0.2 vs. 6.4 ± 0.3 mL O2/min/100 g; P < 0.05). These data demonstrate that administration of supplemental 100% O2 during MV increases diaphragm vascular resistance and diminishes perfusion and O2 delivery to a significantly greater degree than normoxic MV. This suggests that prolonged bouts of MV (i.e., 6 h) with hyperoxia may accelerate MV-induced vascular dysfunction in the quiescent diaphragm and potentially exacerbate downstream contractile dysfunction.NEW & NOTEWORTHY This is the first study, to our knowledge, demonstrating that supplemental oxygen (i.e., 100% O2) during mechanical ventilation (MV) augments the MV-induced reductions in diaphragmatic blood flow and O2 delivery. The accelerated reduction in diaphragmatic blood flow with hyperoxic MV would be expected to potentiate MV-induced diaphragm vascular dysfunction and consequently, downstream contractile dysfunction. The data presented herein provide a putative mechanism for the exacerbated oxidative stress and diaphragm dysfunction reported with prolonged hyperoxic MV.

The application of a surgical face mask over different oxygen delivery devices; a crossover study of measured end-tidal oxygen concentrations.

BACKGROUND: The application of a surgical face mask over oxygen delivery devices is now a widespread recommendation in the setting of the Coronavirus disease pandemic. This addition is designed to reduce droplet spread, but this also changes the nature of these devices, and may alter the amount of oxygen delivered to a patient. This research investigated how placing a surgical face mask over both a simple plastic mask ("Hudson mask") and nasal cannula altered the concentration of available oxygen measured at the nares. METHODS: We measured the inspired and end-tidal oxygen concentrations of five healthy non-smoking volunteers. Oxygen was delivered via nasal cannula and also a simple plastic face mask, at flow rates of 2, 4, 6 and 8 l per minute, with and without an overlying surgical face mask. RESULTS: Adding a surgical mask over nasal cannula caused an appreciable rise in the end-tidal oxygen concentrations at all the measured oxygen flow rates 2, 4, 6, 8 L/minute. With the Hudson mask, there was a rise in oxygen concentration at 4 and 6 L/minute. For example, at a flow rate of 4 l/min via nasal cannula, available oxygen concentration increased from 24 to 36%, and via the Hudson mask the concentration rose from 27 to 38%. CONCLUSIONS: The addition of a surgical face mask over both nasal cannula and a Hudson mask resulted in an increased available oxygen concentration. This may be valuable where more advanced oxygen devices are not available, or alternatively providing adequate supplemental oxygen at lower flow rates and thus making critical savings in oxygen usage.

Humidified and standard oxygen therapy in acute severe asthma in children (HUMOX): A pilot randomised controlled trial.

BACKGROUND: Oxygen (O2) is a mainstay of treatment in acute severe asthma but how it is administered varies widely. The objectives were to examine whether a trial comparing humidified O2 to standard O2 in children is feasible, and specifically to obtain data on recruitment, tolerability and outcome measure stability. METHODS: Heated humidified, cold humidified and standard O2 treatments were compared for children (2-16 years) with acute severe asthma in a multi-centre, open, parallel, pilot randomised controlled trial (RCT). Multiple outcomes were assessed. RESULTS: Of 258 children screened, 66 were randomised (heated humidified O2 n = 25; cold humidified O2 n = 21; standard O2 n = 20). Median (IQR) length of stay (hours) in hospital was 37.9 (29.1), 52 (35.4) and 49.1 (29.7) for standard, heated humidified and cold humidified respectively and time (hours) on O2 was 15.9 (9.4), 13.6 (14.9) and 13.1 (14.9) for the three groups respectively. The mean (standard deviation) time (hours) taken to step down nebulised to inhaled treatment was 5.6 (14.3), 35.1 (28.2) and 32.7 (20.1). Asthma Severity Score decreased in all three groups similarly, although missing data prevented complete analysis. Humidified O2 was least well tolerated with eight participants discontinuing their randomised treatment early. An important barrier to recruitment was research nurse availability. CONCLUSION: Although, the results of this pilot study should not be extrapolated beyond the study sample and inferential conclusions should not be drawn from the results, this is the first RCT to compare humidified and standard O2 therapy in acute severe asthmatics of any age. These findings and accompanying screening data show that a large RCT of O2 therapy is feasible. However, challenges associated with randomisation and data collection should be addressed in any future trial design.

Noninvasive ventilation and high-flow nasal cannula in patients with acute hypoxemic respiratory failure by covid-19: A retrospective study of the feasibility, safety and outcomes.

BACKGROUND: Noninvasive ventilation (NIV) and High-flow nasal cannula (HFNC) are the main forms of treatment for acute respiratory failure. This study aimed to evaluate the effect, safety, and applicability of the NIV and HFNC in patients with acute hypoxemic respiratory failure (AHRF) caused by COVID-19. METHODS: In this retrospective study, we monitored the effect of NIV and HFNC on the SpO2 and respiratory rate before, during, and after treatment, length of stay, rates of endotracheal intubation, and mortality in patients with AHRF caused by COVID-19. Additionally, data regarding RT-PCR from physiotherapists who were directly involved in assisting COVID-19 patients and non-COVID-19. RESULTS: 62.2 % of patients were treated with HFNC. ROX index increased during and after NIV and HFNC treatment (P < 0.05). SpO2 increased during NIV treatment (P < 0.05), but was not maintained after treatment (P = 0.17). In addition, there was no difference in the respiratory rate during or after the NIV (P = 0.95) or HFNC (P = 0.60) treatment. The mortality rate was 35.7 % for NIV vs 21.4 % for HFNC (P = 0.45), while the total endotracheal intubation rate was 57.1 % for NIV vs 69.6 % for HFNC (P = 0.49). Two adverse events occurred during treatment with NIV and eight occurred during treatment with HFNC. There was no difference in the physiotherapists who tested positive for SARS-COV-2 directly involved in assisting COVID-19 patients and non-COVID-19 ones (P = 0.81). CONCLUSION: The application of NIV and HFNC in the critical care unit is feasible and associated with favorable outcomes. In addition, there was no increase in the infection of physiotherapists with SARS-CoV-2.

Mechanisms of the Effects of Short-Term Inhalations of Xe and O2 Gas Mixture in the Rehabilitation of Post-COVID Ventilation Failure.

The article presents a theoretical rationale and a clinical case of relief of post-COVID ventilation failure by inhalation of Xe and O2 gas mixture. Pneumonitis of coronavirus etiology transforms saturated phospholipids of surfactant into a solid-ordered phase, which disrupts surface tension, alveolar pneumatization, and alveolar-capillary gas exchange. Using molecular modeling (B3LYP/lanl2dz; GAUSSIAN09), we demonstrated that Xe atom due to the van der Waals dispersion interaction increases the distance between the phospholipid acyl chains providing a phase transition from the solid-ordered to liquid phase and restored the surface-active monolayer surfactant film. A clinical case confirmed that short-term inhalations of the Xe and O2 gas mixture relieved manifestations of ventilation insufficiency and increased SpO2 and pneumatization of the terminal parts of the lungs.

Impact of exposure time in awake prone positioning on clinical outcomes of patients with COVID-19-related acute respiratory failure treated with high-flow nasal oxygen: a multicenter cohort study.

BACKGROUND: In patients with COVID-19-related acute respiratory failure (ARF), awake prone positioning (AW-PP) reduces the need for intubation in patients treated with high-flow nasal oxygen (HFNO). However, the effects of different exposure times on clinical outcomes remain unclear. We evaluated the effect of AW-PP on the risk of endotracheal intubation and in-hospital mortality in patients with COVID-19-related ARF treated with HFNO and analyzed the effects of different exposure times to AW-PP. METHODS: This multicenter prospective cohort study in six ICUs of 6 centers in Argentine consecutively included patients > 18 years of age with confirmed COVID-19-related ARF requiring HFNO from June 2020 to January 2021. In the primary analysis, the main exposure was awake prone positioning for at least 6 h/day, compared to non-prone positioning (NON-PP). In the sensitivity analysis, exposure was based on the number of hours receiving AW-PP. Inverse probability weighting-propensity score (IPW-PS) was used to adjust the conditional probability of treatment assignment. The primary outcome was endotracheal intubation (ETI); and the secondary outcome was hospital mortality. RESULTS: During the study period, 580 patients were screened and 335 were included; 187 (56%) tolerated AW-PP for [median (p25-75)] 12 (9-16) h/day and 148 (44%) served as controls. The IPW-propensity analysis showed standardized differences < 0.1 in all the variables assessed. After adjusting for other confounders, the OR (95% CI) for ETI in the AW-PP group was 0.36 (0.2-0.7), with a progressive reduction in OR as the exposure to AW-PP increased. The adjusted OR (95% CI) for hospital mortality in the AW-PP group ≥ 6 h/day was 0.47 (0.19-1.31). The exposure to prone positioning ≥ 8 h/d resulted in a further reduction in OR [0.37 (0.17-0.8)]. CONCLUSION: In the study population, AW-PP for ≥ 6 h/day reduced the risk of endotracheal intubation, and exposure ≥ 8 h/d reduced the risk of hospital mortality.